New substituted urea derivatives

ABSTRACT

Substituted urea derivatives having useful antibacterial activity as well as starting materials for their production and methods for preparing the said starting materials; pharmaceutical compositions containing the subject urea derivatives as active ingredient and method for the production of tuberculostatic effects. An illustrative embodiment is 1-(1-adamantyl-3-(3,4dichloro-phenyl)-urea. One starting material variation is the use of 2-oxa-adamantane-1-amines.

United States Patent [72] Inventor Andre R. Gagneux Basel, Switzerland [2|] Appl. No. 882,381

[22] Filed Dec. 3, 1969 [45] Patented Nov. 16, I97i [7 3] Asaignee Gelgy Chemical Corporation Ardlley, NY.

[32] Priorities Nov. 18, 1965 [3 3 1 Switzerland Nov. 18, 1965, Switzerland, No. 15,909/65 Original application Dec. 12, 1968, Ser. No. 783,411, now abandoned. Divided and this application Dec. 3, 1969, Ser. No. 882,381

[54] NEW SUBSTITUTED UREA DERIVATIVES 6 Claims, No Drawings [52] U.S.Cl 260/345.1,

[Sl] Int. Cl C07d 7/18 [50] Field of Search 260/345.1

[56] Reierences Cited OTHER REFERENCES Stetter et aL, Chemiache Berichte, vol. 96, pp. 694- 698 (1963) Primary Examiner-John M. Ford Attorneys- Karl F. Jorda and Bruce M. Collins ABSTRACT: Substituted urea derivatives having useful antibacterial activity as well as starting materials for their production and methods for preparing the said starting materials; pharmaceutical compositions containing the subject urea derivatives as active ingredient and method for the production of tuberculostatic effects. An illustrative embodiment is l-( ladamantyl-3-(3,4-dichlorophenyl)-urea. One starting material variation is the use of Z-oXa-adamantanel -amines.

1 NEW SUBSTITUTED UREA DERIVATIVES CROSS-REFERENCE This in a division of Ser. No. 783,411, filed Dec. 12, 1968 which in turn is a continuation-in-part of Ser. Nos. 593,678 and 593,703, both filed Nov. 14, 1966 and both now abandoned. I

The present invention relates to substituted urea derivatives having valuable pharmacological properties. The invention is further concerned with processes for the production of these substituted urea derivatives and also comprehends certain new amines which are used as starting materials for one such process as well as processes for the production of the said starting materials.

It has been found that the hitherto unknown urea derivatives of the Formula I chloro,

((EH NH R n 1 wherein X, R,, R and n have the meanings given above for Formula I, is reacted with a phenyl isocyanate or isothiocyanate of the Formula Ill R4 (in or with a reactive functional derivative of a carbanilic or thiocarbanilic acid of Formula IV V R2 Rt wherein Y, R R and R, have the meanings given for Formula 1 amides, N-acetyl amides, N,N-diphenyl amides or, particularly when R, is methyl also their chlorides.

The method of the reaction depends on the starting materials used. Reactions vvithphenyl i socyanate s orisothiocyanates 7 Suitable functional derivatives of acids of Formula IV are, e.g., their lower alkyl esters, phenyl esters, amides, N-nitro of the Formula ll! are performed, for example, at temperatures between 0 and instead of isocyanates or isothiocyanates, also compounds can be used which, as isknown, are converted under the reaction conditions into such, for example, 1,3,3-triphenyl ureas the phenyl radical in the l-position of which is, if desired, substituted corresponding to the definition of R and R in this case, the reactions can be performed also at higher temperatures, up to about 250. The amounts of the reaction components can be stoichiometric proportions or an excess of one component can be chosen. They can be added in any order desired, preferably however, the isocyanate is added to the amine. Examples of solvents or diluents which can be used for both reaction components, depending on the reaction temperature necessary, are benzene, toluene, xylene, chlorobenzene, chloroform, carbon tetrachloride, acetone, acetonitrlle, tetrahydrofuran, dioxane and/or diethylene glycol I dimethyl ether, and also lower alkanols can be used for the amines.

Reactions with lower alkyl esters or phenyl esters of carbanilic acids of thiocarbanilic acids of Formula N can be performed at temperatures between 0 and 250 in the absence of solvents or in one of the solvents mentioned above. Reactions with N-nitro amides, i.e., l-phenyl-3-nitro ureas optionally substituted corresponding to the definition of R R and R are performed, e.g. in water or in an aqueous-organic medium such as dioxane/water, at the boiling temperature, and reactions with the amides are performed at temperatures of up to about 200 in the presence or absence of solvents such as glacial acetic acid or phenol. A temperature range of between 0 and about can be used for the reaction of amines of the Formula ll with carbanilic acid chlorides or thiocarbanilic acid chlorides substituted as defined; an excess of the amine to be reacted or a tertiary organic base such as triethylamine, dimethyl aniline or pyridine or also an inorganic base such as sodium hydroxide, sodium or potassium carbonate can be used as acid binding agent and, as solvent, e.g., again one of those mentioned above can be used. Compounds of Formula 1 are obtained by a second process which is related to the first, by reacting an amine of Formula V wherein R R and R, have the meanings give for Formula 1, wi an iiasyat ats et s t qs n fie f th Formula VI or with a reactive functional derivative of a carbamic or t sa bamisasidafli (R5 R4 v wherein X, R R R and n have the meanings given for formula I with a compound of the Formula IX H Y (IX) wherein Y has the meaning given for Formula I.

The addition of water or hydrogen sulfide is effected easily by treatment of a compound of Formula VIII with water or with diluted mineral acids or with a mixture of water or diluted mineral acids and an organic solvent miscible therewith, such as tetrahydrofuran or dioxane, or by passing hydrogen sulfide into a solution which contains compounds of the general Formula VIII in an organic solvent or by treating such a solution with a reagent which gives off hydrosulfide ions such as sodium hydrogen sulfide or sodium sulfide. The reactions mentioned above are performed at temperatures between and 150 depending on the reactivity of the components used and the boiling temperature of any solvent or diluent used.

Finally, certain compounds of Formula I obtained by one of the processes given above can also be converted into other compounds of this formula. In particular, thioureas, i.e. compounds of Formula I wherein Y is sulfur and X, R,, R R R R and n have the meanings given in Formula I, can be converted into the corresponding ureas. Oxidation agents which are suitable for the performance of this variation of the process are, e.g., hydrogen peroxide in solvents miscible with water, sodium peroxide in alkalineaqueous solution, potassium ferricyanide, ferric chloride, potassium permanganate, sodium or potassium hypochlorite in aqueous or aqueous-organic medium.

Of the starting materials of Formula II, l-adamantane amine and tricyclo[4.3. l l lundecane-3 -amine (homoadamantane-l-amine) are known. Compounds of the Formula II wherein n represents 1, X represents oxygen, and R and R are hydrogen or methyl may be prepared by known techniques from the known l-formylor l-acetyI-2-oxa-adamantane.

l-Aminoand l-methylamino-2-oxa-adamantane have not, however, been known hitherto. These compounds may be obtained by a process reacting the reaction mixture of bicyclo[3.3. l ]nonane-3,7-dione and an amine of the Formula wherein R, represents methyl or a-aralkyl, particularly benzyl, or an N-substituted 3-amino-2-oxa-adamantan-l-ol, which can be isolated from the above reaction mixture, of the Formula XI V A L B!L wherein R, has the meanings given above, with a complex hydride, particularly lithium aluminum hydride, the reaction being performed in an organic liquid containing ether oxygen such as tetrahydrofuran, diethyl ether or a mixture thereof, and, when R, represents a-aralkyl, reacting the reaction product with catalytically activated hydrogen to split off this group, so as IOBTtldilEC Q QOITIBOUIICI IIQVIl'lg II'IQFOITIIUIK Ila (Ila) wherein R has the meaning given under Formula I.

The compounds of Formula XI are preferably produced immediately before the reduction by heating the reaction components, bicyclo[3.3. l ]nonane-3,7;dione and an amine of the Formula X, in a solvent which, at the same time, is suitable for the subsequent reduction, e.g., tetrahydrofuran or dibutyl ether. The preferred way of preparation is the immediate reduction of the reaction mixture with a complex hydride; it is, however, possible to isolate first the starting material of the Formula XI and to submit it to reduction in a second reaction step.

The hydrogenolysis which, if necessary, follows the reduction is performed, e.g., in the presence of a noble metal catalyst such as palladium on charcoal, in a suitable organic solvent such as ethanol, under increased pressure and at a raised temperature, e.g., under 20-100 atm. and about 80-l20bL.

The new substituted urea derivatives of Formula I can be administered orally and also parenterally in the usual dosage forms. Suitable forms for oral administration are, e.g., tablets, dragees (sugar coated tablets) and gelatine capsules. For parenteral administration, e.g., solutions and dispersions in mixtures of water and suitable solubility promoters and/or emulsifying agents can be used and, particularly for intramuscular administration, also solutions in suitable fatty oils can be used. The compounds of Formula I are of particular importance for the local therapy of above diseases where they also can be applied in forms not make up into single dosages such as ointments, powders and aerosols.

Dosage units for oral administration preferably contain between about 0.3 g. and about 10 g. of a compound as defined in Formula I. They are produced, e.g., by combining the active substance with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, op-

tionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols (carbowax) of suitable molecular weights, to form tablets or dragee cores. The latter may be coated with concentrated sugar solutions which can also contain e.g., gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in easily voltaile organic solvents or mixture of solvents. Dyestuffs can be added to these coatings, e.g., to distinguish between varying dosages of active substance.

Ampuls for parenteral, particularly intramuscular adminis' tration preferably contain an oil-soluble compound as defined in Formula I in a concentration of, preferably, 10 percent in oily solution to which suitable stabilizing agents and buffer substances may be added.

Pharmaceutical compositions for local therapy are prepared by mixing a compound as defined in Formula I with a suitable carrier, e.g., Vaseline. The active substance should be present ina conce itration of, preferably, 5 percent.

As mentioned above, the subject compounds possess valuable pharmacological properties in mammals; they can be characterized as antibacterial agents, especially as tuberculostatic agents.

tions, to a culture medium (Youmars serum agar) which was 5 subsequently inoculated with human tuberculosis bacteria. The cultures were then incubated for 18 days at 37 C. In this way the minimum concentration of test substance in the culture medium, required to prevent culture growth, was determined.

The following compounds:

a. l'( l-Adamantyl)-3-(3,4-dichlorophenyl)'urea b. l-( l-Adamantyl)-3-(4-chlorophenyl)-urea c. l-( l-Adamantyl)-3-(p-tolyl)-urea d. l-( l-Adamantyl )-3-(01,01,01-trifluor-4-chlor-m-tolyl)-urea and e. l-( Adamanl -yl )-3-( 3 ,4-dichlorophenyl )-urea were found to have an excellent inhibitory effect on the growth of type humanus (A5 and an isoniocotinic acid hydrazide resistant mutant (H37Rv) thereof, at low concentrations.

Illustratively, the acute toxicity was determined for l-(ladamantyl)-3-(3-trifluoromethyl-4-chlorophenyl)-urea and l- (l-adamantyl)-3-(4-methylphenyl)urea. The LD on oral administration to mice was higher than 400 mg./kg. in a single dose for l-( l-adamantyl)-3-(3-trifluoromethyl-4-chlorophenyl)-urea and higher than 400 mgJkg. for l-(l-adamantyl)-3 (4-methyl-phenyl)urea.

This invention contemplates a method for producing antibacterial, especially tuberculostatic effects which comprises administering to a mammal suffering from tuberculosis a therapeutic dose of a compound of Formula I. For the intended use, the compounds of the present invention are administered in dosages of from to 100 mgJkg. p.o.

Also contemplated by this invention is a composition for producing antibacterial, especially tuberculostatic effects comprising a pharmaceutical carrier and a compound of Formula l in the method described above, in dosage unit forms acceptable for internal administration.

The following examples illustrate the production of the new substituted urea derivatives of Formula I and of hitherto unknown intermediate products, but the scope of the invention is in no way limited thereto. The temperatures are given in degrees Centigrade.

EXAMPLE I 5.5 g. (36.5 mM) of l-adamantane amine in 100 ml. of abs. benzene and 6.25 g. (33.3 mM.) of 3,4-dichlorophenyl isocyanate are both added to 100 ml. of the same solvent whereupon heat is generated and crystals are formed. The mixture is heated for 1 hour at 80, then cooled and filtered. The filter e. l-( l-adamantyl)-3-(o-methoxyphenyl)-urea, M.P.

234-236; f. l-( l-adamantyl)-3-(p-methoxyphenyD-urea, M.P.

g. l-(l-adamantyl)-3-(2,5-dimethoxyphenyl)-urea, M.P.

h. l-( l-adamantyl)-3-(m-acetylphenyl)-urea, M.P. 200-20 i. 1-(l-adamantyl)-l-methyl-3-(3,4-dichlorophenyl)-urea,

M.P. l93-195; j. l-(tricyclo[4.3. l l ]undec-3-yl)-3-( 3,4-dichlorophenyl)-urea, M.P. 233236.

EXAMPLE 2 5.0 g. (33 mM.) of l-adamantane amine in 50 ml. of abs. toluene are added to 5.70 g. (28 mM.) of 3,4-dichlorophenyl isothiocyanate in 50 ml. of abs. toluene whereupon heat is generated and crystals are formed. The mixture is heated for 1 hour on a steam bath, cooled, filtered and the precipitate is washed with ether. The solid phase is stirred in ml. of 1N hydrochloric acid and 20 ml. of methanol, filtered off, washed with water until the washing water is neutral and finally recrystallized from dioxane/ethanol: l-( l-adamantyl)-3-(3,4- dichloro phenyl)-2-thiourea, M.P. l93l95.

The following 2-thioureas are obtained analogously on using, e.g. the corresponding substituted phenyl isothiocyanates and l-adamantane amine:

a. l-(l-adamantyl)-3-(p-chlorophenyl)-2-thiourea,

b. l-( l-adamantyl)-3-(2,4-dichlorophenyl)-2-thiourea,

thiourea, M.P. l69-17 1.

EXAMPLE 3 l-(2-Oxa-adamant-l-yl)-3-(3,4-dichlorophenyl)-urea, M.P. 208-2 10, is obtained analogously to example 1 starting from 5.1 g. (33 mM.) of 2-oxa-adamantane-l-amine and 5.65 g. (30 mM.) of 3,4-dichlorophenyl isocyanate.

The 2-oxa-adamantane-l-amine used as starting material is produced, e.g., as follows:

a. 7.60 g. (50 mM.) of bicyclo[3.3.l]nonan-3,7-dione (produced according to H. Stetter et al., Chem. Ber. 96, 694-698 (1963)) and 5.35 g. (50 mM.) ofbenzylamine in 300 ml. of abs. tetrahydrofuran are refluxed for 30 minutes. After cooling, this mixture, which contains 3- benzylamino-Z-oxa-adamantan- 1 -ol, is added dropwise to 3.80 g. (100 mM.) of lithium aluminum hydride in 100 ml. of abs. ether while stirring vigorously. The whole is then stirred for 6 hours at a bath temperature 40 and then, while cooling with ice, [9 ml. of 1N sodium hydroxide solution are slowly added dropwise. The precipitate formed is filtered off through Hyflo. The clear filtrate is evaporated, the residue is dissolved in 500 ml. of acetone and 5 ml. of concentrated hydrochloric acid are added' whereupon the hydrochloride crystallizes immediately. The hydrochloride is filtered off, washed with cold acetone, dried for 6 hours under 12 torr and N-benzyl-2- oxa-adamantane-l-amino hydrochloride is obtained; it melts at 242245.

b. 9.30 g. (33 mM.) of N-benzyl-2-oxa-adamantane-lamine hydrochloride in 100 ml. ethanol and in the presence of 2.0 g. of 5 percent palladium charcoal are kept for 2 hours at l00 under a hydrogen pressure of 50 atm. After cooling, the catalyst is filtered off, the filtrate is evaporated, 25 ml. of concentrated sodium hydroxide solution are added to the residue which is then extracted with 200 ml. of ether. The ether solution is dried over potassium carbonate and concentrated and the residue is sublimed at 60 under 0.1 torr. Z-OXa-adamantane-I- amine (M.P. l48-l54) is obtained. The hydrochloride melts at 280.

EXAMPLE 4 A solution of 2.4 g. 10 mM.) of N-methyl-N-(3,4-dichlorophenyl)-ehloroform amide in 50 ml. of abs. benzene is added dropwise to a solution of 3.32 g. (22 mM.) of l -adamantane amine in 50 ml. of abs. benzene. The reaction mixture is heated to reflux temperature whereupon l-adamantane amine hydrochloride begins to separate out. After refluxing for 8 hours, the reaction mixture is cooled and the precipitate is filtered off. The filtrate is extracted twice with 50 ml. of 1N hydrochloric acid each time and then twice with 50 ml. of water each time, dried over sodium sulfate and concentrated to dryness. After recrystallizing the residue from cyclohexane/hexane, 1-( l-adamantyl)-3-(3,4-dichlorophenyl)-3- methyl urea is obtained, MP. l80-l 82.

EXAMPLE 5 A solution of 0.99 g. (6 mM.) of l-admantane methylamine is added to a solution of 1.13 g. (6 mM.) of 3,4-dichlorophenyl isocyanate in ml. of abs. toluene. After heating for 2 hours on a steam bath, it is cooled whereupon crystals separate out. These are filtered off, washed with toluene and recrystallized from ethanol. The l-( ladamantyl)-l-methyl-3-(3,4-dichlorophenyl)-urea so obtained melts at l89l9 1".

EXAMPLE EXAMPLE 7 885 mg. (5 mM.) of l-adamantane isocyanate and 535 mg. (5 mM.) of p-toluidine are dissolved in ml. of abs. benzene and the solution is refluxed for 15 hours. After cooling, the crystals which separate are filtered off under suction at room temperature and washed with benzene. l-( l-adamantyl)-3-(ptolyl)-urea melts at 254255.

EXAMPLE 8 680 mg. of percent hydrogen peroxide dissolved in 10 ml. of methanol are added to the suspension of 710 mg. of 1- (adamantyl)-3-(3,4-dichlorophenyl)-thiourea in 10 ml. of methanol. The mixture is refluxed and, after 30 minutes, a clear solution is formed. After another 30 minutes, 10 ml. of water are added dropwise to the hot solution. The product which precipitates, l-(l-adarnantyl)-3-(3,4-dichlorophenyl)- urea, is filtered off hot and recrystallized from 80 percent ethanol. It melts at 2l8-221.

EXAMPLE 9 1.77 g. (5mM.) of l( l-adamantyl)-3-(3,4-dichlorophenyl)- thiourea are dissolved at 30 in 180 ml. of purified dioxane. 18 ml. of water and, finally, 9 g. of lead oxide (PbO) mM.) are added. The whole is stirred, first for 15 hours at room temperature and then for 3 hours at reflux temperature. The reac tion mixture is filtered hot through l-lyflo. Water (220 ml.) is added to the hot filtrate until it remains opaque. On cooling, crystals separate out. After recrystallization from ethanol, the

l-( l-adamantyl)-3-(3,4-dichlorophenyl)-urea melts at 2l5220.

EXAMPLEIO 200 mg. (0.62 mM.) of l-(l-adamantyl)-3-(3,4-

dichlorophenyl)-carbodimide, 15 ml. of dioxane and 5 ml. of 0. l N hydrochloric acid are refluxed together for 1 hour. After cooling, at little water is added and the crystals which separate are filtered off. Recrystallization from ethanol yields l-( l-adamantyl)-3( 3,4dichlorophenyl)-urea; MP. 220-224.

The l-( l-adamantyl )-3-( 3,4-dichlorophenyl)-carbodiimide necessary for the reaction described above is produced as follows:

5.32 g.( 15 mM.) of l-(l-adamantyl)-3-(3,4-dichlorophenyl)-thiourea are dissolveu at room temperature in 600 ml. of abs. dioxane. Then 6 g. (50 mM.) of anhydrous magnesium sulfate and finally 26.8 g. (120 mM.) of lead oxide (PbO) are added. The whole is stirred for 15 hours at 60, then cooled and filtered through Hyflo. The clear, colourless filtrate is concentrated to dryness in vacuo. The oily residue is taken up in 300 ml. of pentane. The opaque solution is clarified by filtration through active charcoal and then concentrated whereupon crude l-(l-adamantyl )-3-( 3 ,4-dichlorophenyl )-carbodiimide crystallizes out. After crystallization from pentane at -1 5, pure product which melts at 60-6l is obtained.

EXAMPLE 1 1 Hydrogen sulfide is introduced for 3hours into the boiling solution of 321 mg. (1 mM.) of l-adamantyl)-3-(3,4- dichlorophenyl)-carbodiimide in 10 ml. of absdioxane. The yellow reaction solution is concentrated to dryness. The yellow residue is washed twice with 5 ml. of ethanol each time whereupon the insoluble part, l-( l-adamantyl)-3,4- dichlorophenyl)-thio-urea crystallizes; MP. 1 89192.

EXAMPLE 12 a. Tablet Preparation 1,000 g. of 1-(1-adamantyl)-3-(3,4-dichlorophenyl)-urea chlorohydride were mixed with 351.60 g. of lactose and 339.40 g. of potato starch. The mixture was moistened with an alcoholic solution of 20 g. stearic acid and granulated through a sieve. After drying the granulate was mixed with 320 g. of potato starch, 400 g. of talcum, 5.0 g. of magnesium stearate and 64 g. of colloidal silica and the mixture was pressed out into 110,000 tablets weighing 250 mg. and containing mg. of active substance each. The tablets may be grooved for better adaptation of the dosage.

b. Suppository Preparation 0.10 g. of 1-( l-adamantyl)-3-(3,4-dichlorophenyl)urea were mixed with 2.00 g. of parafin oil of low viscosity, and the mixture was added to a liquid mass of 10.00 g. animal fat and white Vaseline to give a total weight of 10000 g. The mixture was then allowed to solidify with stirring and shaped.

What is claimed is:

l. A compound of the formula l. wherein R, is hydrogen, methyl or benzyl.

2. A compound as defined in claim 1 wherein R, is hydrogen.

3. A compound as defined in claim 1 wherein R, is methyl. 4. A compound as defined in claim l wherein R, is benzyl. 5. Process for preparing new amines of the formula wherein R is hydrogen, methyl or benzyl, which comprises reacting the reaction mixture of bicyclo|(3.3.l nonane-3,7- dione and an amine corresponding to the general formula O NH-Re wherein R is hydrogen, methyl or benzyl which comprises reacting an N-substituted 3 amino-2-oxa-adamantan-l-ol of the formula HO 0 NH-Rs wherein R is methyl or benzyl with a complex hydride, particularly with lithium aluminum hydride, in an organic liquid containing ether oxygen and, if desired, when R is a benzyl reacting the product thus obtained with catalytically activated hydrogen to split off this group. 

2. A compound as defined in claim 1 wherein R1 is hydrogen.
 3. A compound as defined in claim 1 wherein R1 is methyl.
 4. A compound as defined in claim 1 wherein R1 is benzyl.
 5. Process for preparing new amines of the formula
 6. Process for preparing new amines of the formula 